Anorectic compositions containing n-thienylalky-b-alkoxy-trifluoromethylphenylalkyl-amines and methods of use

ABSTRACT

N-Thienyalkyl- Beta -alkoxy-trifluoromethylphenalkylamines having anorectic activity are prepared by condensation of an Nthienylalkylamine with a Beta -alkoxy-trifluoromethylphenalkyl halide.

United States Patent [191 Laiferty et al.

[ ANORECTIC COMPOSITIONS CONTAINING N-THIENYLALKY-B-ALKOXY- TRIFLUOROMETHYLPl-IENYLALKYL- AMINES AND METHODS OF USE [75] Inventors: John J. Lafferty, Levittown; Charles L. Zirkle, Berwyn, both of Pa.

[73] Assignee: Smithkline Corporation,

Philadelphia, Pa.

[22] Filed: Sept. 28, 1972 [21] App]. No.: 293,277

Related US. Application Data [62] Division of Ser. No. 72,111, Sept. 14, 1970, Pat. No.

[52] US. Cl. 424/275, 424/360 Oct.9,1973

[51] Int. Cl. A61! 27/00 [58] Field of Search 424/275 [56] References Cited UNITED STATES PATENTS 3,226,440 12/1965 Sayun et a1. 260/5706 3,459,803 8/1969 Faust et a1. 260/570.6

Primary Examiner-Albert T. Meyers Assistant ExaminerNorman A. Drezin Att0rneyWilliam H. Edgerton et al.

[57] ABSTRACT N-Thienyalkyl-B-alkoxy-trifluoromethylphenalkylamines having anorectic activity are prepared by condensation of an N-thienylalkylamine with a B-a1koxytrifluoromethylphenalkyl halide.

11 Claims, No Drawings ANORECTIC COMPOSITIONS CONTAINING N-THIENYLALKY-B-ALKOXY- TRIFLUOROMETHYLPHENYLALKYL-AMINES AND METHODS OF USE This is a division of U.S. Pat. application Ser. No.

72,111 filed Sept. 14, 1970 now U.S. Pat. No. 3,709,913.

This invention relates to a novel series of N- thienylalkyl-B-alkoxy-trifluoromethylphenalkylamines which have useful pharmacodynamic activity. More specifically, these compounds have utility as anorectic agents, that is, they produce a significant decrease in body weight accompanied by anorexia with little or no side effects.

The compounds of this invention may be represented by the following structural formula:

FORMULA I in which R represents lower alkyl of from one to three carbon atoms, preferably methyl;

R represents hydrogen or methyl;

R represents hydrogen or lower alkyl of from one to three carbon atoms; and

A represents a lower alkylene chain, straight or branched, of from one to three carbon atoms.

Preferred compounds of this invention are represented by the following structural formula:

FORMULA II in which R and R are each hydrogen or methyl.

The compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well knwon to the art, are formed with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

To prepare the compounds of this invention a trifluoromethyl substituted B-alkoxyphenalkyl halide is condensed with a thienylalkylamine. Conveniently, when a tertiary amino product is desired, an N-alkyl-N- thienylalkylamine and the phenalkyl halide, preferably bromide, are condensed in a nonreactive organic solvent such as benzene, toluene or xylene, in the presence of an alkali metal carbonate, for example potassium carbonate, at reflux temperature for from 4 to 12 hours. When a secondary amino product is desired, the phenalkyl halide is advantageously condensed with an .methoxy-( 3 '-trifluoromethylphenyl)-ethylamine,

excess of the thienylalkylamine at about 100 C. for from 1 to 3 hours.

Racemic mixtures of the compounds of this invention are thus prepared as a result of the asymmetric substitution of one or more carbon atoms. Such mixtures can be resolved by fractional crystallization of an optically active salt of the amine products. Unless otherwise noted it is intended to include in the structural formulas set forth herein and in the claims, both the racemic mixtures as well as the separated d and l isomers.

The preparation of the appropriately substituted B-alkoxyphenalkyl halides used as starting materials above is described in U.S. Pat. Nos. 3,226,440 and 3,459,803.

The anorectic activity of the compounds of this invention is demonstrated by a standard pharmacological procedure as follows. Compounds are tested orally for their ability to quantitatively reduce first hour food consumption of rats trained to consume their daily food requirements in only 6 hours. A preferred compound of this invention, N-methyl-N-(2"-thienylmethyl)-B- has an oral anorectic ED in rats of 2.6 mg/kg.

Of particular significance is the low sedation potential of compounds of this invention at effective anorectic dose levels. Sedation potential is demonstrated in a confinement motor activity procedure. In this pharmacological procedure, compounds are tested for their ability to induce a graded depression or stimulation of exploratory motor activity of rats maintained in a confined area. The DD is defined as the dose of compound which causes a 50 percent decrease in the average l5 minute counts of treated animals below the average 15 minute counts of control animals. The same compound noted above has a DD of 27.7 mg/kg. The ratio between the confinement motor activity DD for this compound and its ED in the rat anorexia test is approximately 10.6 to l (27.7/2.6). Large ratios such as this indicate a low potential to produce sedation at anorectic dose levels for compounds of this invention.

To obtain anorectic activity the compounds of this invention may be administered orally or parenterally to an animal organism in conventional dosage unit forms.

Preferably a compound or an acid addition salt thereof is administered orally in a tablet or capsule. The dosage units are prepared by incorporating the active medicament in an amount sufficient to produce anorectic activity with a nontoxic pharmaceutical carrier according to accepted procedures. Preferably each dosage unit will contain the active medicament in an amount of about 10 mg. to about mg. Advantageously equal doses will be administered two to four times daily with the daily dosage regimen being about 20 mg. to about 300 mg.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra' alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium, stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent can include any time delay material well known to the art, such as glyceryl monstearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or 102- enge. The amount of solid carrier will vary widely but preferably will be about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.

The following examples illustrate more specifically how to prepare compounds of this invention. However, as such, they are not to be construed as limiting the scope of the invention as defined in formulas l and I1 above.

EXAMPLE 1 A mixture of 5.40-g. (0.0425 m.) of N-methyl-2- thienylmethylamine, 18 ml. of xylene, 2.94 g. (0.0213 in.) of powdered potassium carbonate and 12.00 g. (0.0425 in.) of B-methoxy-(3'-trifluoromethylphenyl)- ethyl bromide is stirred at reflux (148 C.) for 5 and A hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure. The residue is vacuum distilled to give the free base, N-methyl-N-(2"- thienylmethyl)-fi-methoxy-(3-trifluoromethylphenyl)- ethylarnine, b.p. l05l2l.5 C./0.10 mm.; hexamate, m.p. ll51 16 C.

Similarly, reaction of N-methyl-2- thienylmethylamine with B-ethoxy-( 3-trifluoromethylphenyl)-ethyl bromide as described above yields N- methyl-N-(Z"-thienylmethyl) -B-ethoxy- (3 -tritluoromethylphenyl)-ethylamine.

EXAMPLE 2 A mixture of 24.10 g. (0.0853 m.) of B-methoxy-(3- trifluoromethylphenyl)-ethyl bromide and 28.98 g. (0.2560 in.) of 2-thienylmethylamine is stirred and heated at 95100 C. for 2 hours. The cooled reaction mixture is made basic with aqueous sodium hydroxide and extracted with ether. The extract is concentrated and the residue is taken up in concentrated hydrochloric acid and ether to give a three-layer system. The upper layer is removed and the remainder is extracted with ether. The combined ether extract is concentrated to give 3-trifluoromethylacetophenone.

The lower two phases are treated with excess aqueous ammonia and extracted with ether. The dried ether extract is concentrated and the residue is vacuum distilled to give the free base, N-(2"-thienylmethyl)-fimethoxy-(3'-trifluoromethylphenyl) ethylamine, b.p. 117-126C./0.05 mm.;hydrochloride, m.p. 127-l29 EXAMPLE 3 Following the procedure of Example 1, N-methyl-Z- thienylmethylamine is reacted with B-methoxy-(2-trifluoromethylphenyl)-ethyl bromide to give N-methyl- N-(2-thienylmethyl)-/3-methoxy-(2'-trifluoromethylphenyl)-ethylamine.

Similar reaction with B-methoxy-(4-trifluoromethylphenyl)-ethyl bromide yields the corresponding N- methyl-N-(2"-thienylmethyl)-B-methoxy-(4'- trifluoromethylphenyl)-ethylarnine.

EXAMPLE 4 Following the procedure of Example 2, 2- thienylethylamine is reacted with l-methoxy-l-(3'- trifluoromethylphenyl)-2-propyl bromide to give N- (2' '-thienylethyl l -methoxyl 3 '-trifluoromethylphenyl)-2-propylamine.

. EXAMPLE 5 Ingredients Mgfl'ablet N-m ethyl-N-( 2 -thienylmethyl B-m ethoxy-( 3'-trifluoromethylphenyl )-ethylamine Calcium sulfate, dihydrate l2 5 Sucrose 25 Starch l 5 Talc S Stearic Acid 3 EXAMPLE 6 Ingredients MgJCapsule N-(2'"thienylmethyl)-fl-methoxy- 5O (3 -trifluoromethylphenyl )-ethyl amine Magnesium stearale 5 Lactose 325 The active medicament (as the hydrochloride) and other ingredients above are screened through a No. 40 mesh screen, mixed and filled into No. 0 hard gelatin capsules.

What is claimed is:

1. An anorectic composition in dosage unit form comprising an anorectically effective amount of a compound of the formula:

on R l H J CFa i i l in which:

R is lower alkyl of from one to three carbon atoms;

R is hydrogen or methyl;

R is hydrogen or lower alkyl of from one to three carbon atoms; and

A is a lower alkylene chain, straight or branched, of from one to three carbon atoms or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical carrier.

2. The composition of claim 1 in which the CF group is in the meta position.

3. The composition of claim 2 in which the thiophene ring is 2-substituted.

4. The composition of claim 3 in which R is methyl.

5. The composition of claim 4 in which A is methylene.

6. The composition of claim 5 in which R, is hydrogen. 7

7. The composition of claim 6 in which R is methyl.

8. The composition of claim 6 in which R is hydrogen.

9. The composition of claim 1 in which the active medicament is in an amount of about 10 mg. to about mg. per dosage unit.

10. A method of producing anorectic activity in an animal organism in need thereof which comprises administering orally or parenterally to said animal organism in an amount sufficient to produce said activity a compound as defined in claim 1.

11. The method ofclaim 10 in which the active medicament is administered in a daily dosage regimen of about 20 mg. to about 300 mg.

i h i l 

2. The composition of claim 1 in which the CF3 group is in the meta position.
 3. The cOmposition of claim 2 in which the thiophene ring is 2-substituted.
 4. The composition of claim 3 in which R is methyl.
 5. The composition of claim 4 in which A is methylene.
 6. The composition of claim 5 in which R1 is hydrogen.
 7. The composition of claim 6 in which R2 is methyl.
 8. The composition of claim 6 in which R2 is hydrogen.
 9. The composition of claim 1 in which the active medicament is in an amount of about 10 mg. to about 75 mg. per dosage unit.
 10. A method of producing anorectic activity in an animal organism in need thereof which comprises administering orally or parenterally to said animal organism in an amount sufficient to produce said activity a compound as defined in claim
 1. 11. The method of claim 10 in which the active medicament is administered in a daily dosage regimen of about 20 mg. to about 300 mg. 